The objective of the research proposed in this application is to assess the importance of sex-and estrous-related differences in immunity when considering surgery and pain management options for women with breast cancer. The 3 specific aims are: (1) to assess the sex-and estrous- related differences in the immune suppressive effects of surgery; (2) to characterize the sex- and estrous-related differences in the metastatic- enchaining effects of surgery; and (3) to investigate sex- and estrous- related differences in the effectiveness of morphine in blocking surgery- induced enhancement of metastasis. To investigate these issues, the MADB106 tumor model, a mammary adenocarcinoma syngeneic to the inbred Fischer 344 rats to be studied, will be used. Both the lung clearance and metastatic colonization of this tumor are controlled by natural killer (NK) cell function, matching what is known about the metastatic process in humans. To assess for sex and estrous effects on surgery- induced suppression of NK cytotoxic activity and enhancement of tumor cell retention, female and males rats will be grouped by sex and estrous phase (females), and undergo either abdominal surgery with halothane anesthesia or no treatment. After surgery, animals will undergo either blood withdrawal for in vitro assessment of NK cytotoxic activity or intravenous injection of radiolabeled MADB106 tumor cells to assess lung clearance. To investigate sex- and estrous-related differences in the beneficial effects of morphine on surgery-induced enhancement of tumor cell retention, animals grouped by sex and estrous phase will undergo abdominal surgery with anesthesia or anesthesia alone, and will be treated or not with morphine. After surgery, the lung clearance of radiolabeled MADB106 tumor cells will be assessed. With regard to the health relatedness of this project, the findings of these studies could lead to a better understanding of whether and how the timing of surgical interventions with respect to the menstrual cycle impact long term sequelae in breast cancer patients. Additionally, this work has the potential to demonstrate an aversive consequence of inadequate pain relief in females undergoing surgery for breast cancer.